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Methods and compositions for treating glucose-associated conditions, metabolic syndrome, dyslipidemias and other conditions

a technology of boroproline and composition, which is applied in the field of compositions of glutamic acid boroproline containing compounds, can solve the problems of limited incretin effect of both hormones, achieve the effects of reducing body weight, preventing weight gain, and reducing body weigh

Inactive Publication Date: 2006-05-04
DARA BIOSCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008] The invention also relates to the use of Glu-boroPro containing compounds in the treatment (and prevention) of conditions that are not necessarily glucose-associated such as metabolic syndrome, dyslipidemias, and cardiovascular disorders. The compounds can also be used to prevent weight gain or to reduce body weight in subjects who may or may not be obese.
[0009] The compounds of the invention are also useful in lowering the levels of triglycerides, free fatty acids, C-reactive protein (CRP), HbA1C, and / or total glycosylated hemoglobin (TGHb) in a subject. The compounds of the invention are also useful in increasing the insulin sensitivity index in a subject, stimulating insulin release from the pancreas, and reducing food intake by a subject.
[0019] In one embodiment the effective amount is an amount that reduces blood glucose at least 40% relative to an untreated subject.
[0045] In some embodiments controlling body weight of a subject comprises reducing the body weight of the subject. In other embodiments, controlling body weight comprises preventing body weight gain in the subject.
[0076] According to another aspect of the invention, a method for stimulating insulin release from a pancreatic cell is provided. The method comprises contacting a pancreatic cell with a Glu-boroPro containing compound in an effective amount to stimulate insulin release from the pancreatic cell and increase insulin level.

Problems solved by technology

The incretin effect of both hormones is limited in vivo, however, because they are rapidly inactivated by the serine protease DPP-IV.

Method used

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  • Methods and compositions for treating glucose-associated conditions, metabolic syndrome, dyslipidemias and other conditions
  • Methods and compositions for treating glucose-associated conditions, metabolic syndrome, dyslipidemias and other conditions
  • Methods and compositions for treating glucose-associated conditions, metabolic syndrome, dyslipidemias and other conditions

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0310] This example illustrates the kinetics of in vitro DPP-IV inhibition by Glu-boroPro. The enzyme inhibitory activity of Glu-boroPro is compared with that of other amino boronic dipeptides in in vitro assays with isolated DPP-IV.

Materials and Methods

[0311] Production of soluble recombinant human DPP-IV. Based on information on the N-terminus of serum DPP-IV (15), a truncated DPP-IV was engineered in which a signal / leader sequence was joined to the residue in DPP-IV corresponding to the N-terminus of serum DPP-IV to allow secretion. The cDNA encoding the desired truncated human DPP-IV dimer enzyme was engineered into the mammalian secretion vector pSecTag2 (Cat# V900-20, InVitrogen Corporation). The vector, available in A, B or C versions, representing three possible phases for gene fusion, contained an immunoglobulin-kappa light chain secretion signal followed by a selection of restriction sites for gene insertion. The fusion required engineering a restriction site upstream o...

example 2

[0317] This example illustrates the kinetics of serum DPP-IV inhibition by Glu-boroPro in vivo in mice. The enzyme inhibitory activity of Glu-boroPro is compared with that of other amino boronic dipeptides in in vitro assays with isolated DPP-IV.

Materials and Methods

[0318] Assay of serum DPP-IV inhibition in vivo. Varying doses (0.02, 0.2, 2.0, 20.0 μg / mouse) of Glu-boroPro dissolved in normal saline or the saline vehicle alone were administered to BALB / c mice by oral gavage. Each mouse received a single administration of Glu-boroPro or saline, and blood samples were withdrawn from mice 2 hours later. In studies of the duration of DPP-IV inhibition after administration of 5 or 10 μg / mouse of Glu-boroPro, blood samples were withdrawn at 1, 2, 4, 6, 11, 24, 26 and 48 hours after Glu-boroPro or saline administration. DPP-IV activity was determined by reaction of 10 μl serum with 90 μl of 0.11 mM Ala-Pro-AFC (Enzyme System Products, Dublin, Calif.) in 50 mM HEPES / Na buffer pH 7.6, 14...

example 3

[0320] This example illustrates that, unlike the amino boronic peptides Val-boroPro, Ile-boroPro and Leu-boroPro, Glu-boroPro does not appear to stimulate cytokine production by cultured human bone marrow stromal cells in vitro, as indicated by measurement of the levels of granulocyte colony stimulating factor (G-CSF) in culture supernatants. G-CSF was assayed because it was previously shown to be an indicator of increased levels of cytokines in stromal cell cultures stimulated with Val-boroPro (16).

Materials and Methods

[0321] Human bone marrow stromal cell cultures. Samples of normal human bone marrow were purchased from Cambrex Bioproducts (Walkersville, Md.) and mononuclear cells were purified over Ficoll-Hypaque (Nycomed, Oslo, Norway). Human stromal layers were established by seeding 4×107 mononuclear cells into T75 flasks (Corning) containing 20 ml MyeloCult medium (Stem Cell Technologies, Vancouver, BC) supplemented with 10−6 M hydrocortisone (Sigma) and incubation at 37° ...

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Abstract

The invention relates, in part, to of Glu-boroPro containing compounds and methods of use thereof in the prevention or management of conditions that are associated with impaired glucose tolerance such as diabetes. The invention also relates to compositions of Glu-boroPro containing compounds and methods of use thereof in the prevention or management of conditions such as metabolic syndrome, dyslipidemias, inflammation, cardiovascular disorders such as hypertension and atherosclerosis, and to reduce body weight or prevent weight gain. The compounds of the invention are also useful in lowering levels of triglycerides, free fatty acids, C-reactive protein (CRP), HbA1C, total glycosylated hemoglobin (TGHb), in increasing insulin sensitivity index and in stimulating insulin release.

Description

RELATED APPLICATIONS [0001] This application claims priority under 35 U.S.C. § 119(e) from U.S. provisional application Ser. No. 60 / 704,157, filed Jul. 29, 2005, and from U.S. provisional application Ser. No. 60 / 700,871, filed Jul. 19, 2005, and from U.S. provisional application Ser. No. 60 / 622,466, filed Oct. 27, 2004, and from U.S. provisional application Ser. No. 60 / 612,069, filed Sep. 21, 2004.FIELD OF THE INVENTION [0002] The invention relates, in part, to compositions of glutamic acid boroproline containing compounds and uses thereof for the treatment and prevention of conditions that are associated with impaired glucose tolerance, such as type 2 diabetes and other conditions such as metabolic syndrome, dyslipidemias, cardiovascular disorders, inflammation and obesity. BACKGROUND OF THE INVENTION [0003] Type 2 diabetes accounts for 90-95 per cent of all diabetes and results from insulin resistance in muscle and impaired function of the pancreatic beta (β)-cells that produce in...

Claims

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Application Information

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IPC IPC(8): A61K31/69
CPCA61K31/69A61K38/28
Inventor AZIZ, NAZNEENJESSON, MICHAELMCLEAN, PAULMILLER, GLENNJONES, BARRY
Owner DARA BIOSCI
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